Ethyl Acetate → 6beta-Hydroxynaltrexone

HRID 1741992Notes

Reaction equation

HRID 1741992 reaction equation
[CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C:20]([CH2:22][CH2:23][C@@:9]34[OH:24])=[O:21])[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.C(S(O)=O)(N)=N.[Cl-].[NH4+].C(OCC)(=O)C>[OH-].[Na+].O>[CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C@H:20]([OH:21])[CH2:22][CH2:23][C@@:9]34[OH:24])[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 25517Ammonium ChlorideHCID 61274Thiourea dioxideHCID 5360515Naltrexone

Product 1

HCID 54865546beta-HydroxynaltrexoneYield 89%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 14798Sodium HydroxideSolvent

Procedure

To a suspension of naltrexone base 3 (6.81 g, 20.0 mmol) (Mallinckrodt, St. Louis, Mo.), under argon was added 100 ml (enough to afford complete solution) of 0.533M aqueous NaOH. The alkaline solution of naltrexone was treated dropwise at ambient temperature during 20 min. with 8.64 g (80 mmol) of formamidinesulfinic acid dissolved in 200 ml of 0.533M aqueous NaOH. After the addition was complete, the solution was heated and stirred at 80°-85° C. for 1.5 h when TLC indicated the reaction to be complete. The reaction mixture was cooled (ice-bath) and then treated dropwise under argon with a solution of ammonium chloride (10.27 g, 192 mmol) in distilled water (100 ml). The aqueous mixture was extracted with 5×100 ml of CHCl3 and the combined organic extract was filtered through a pad of Na2SO4 and evaporated in vacuo to afford crude 5.(base) as a foam which was dissolved in 20 ml of warm (50° C.) ethyl acetate and diluted to 60 ml with warm n-hexanes. Crystallization occurred spontaneously on cooling. The crystals were collected by filtration, washed with 2×10 ml of cold ethyl acetate/n-hexanes (1:3), and oven dried in vacuo at 60° C. to give 5 (6.11 g, 89%) (free of any 6α-epimer 4): [α]D =-156° (c 0.604, MeOH). mp 707°-708° C.

Workup

  1. additionAfter the addition
  2. temperaturethe solution was heated
  3. customthe reaction
  4. temperatureThe reaction mixture was cooled (ice-bath)
  5. extractionThe aqueous mixture was extracted with 5×100 ml of CHCl3
  6. extractionthe combined organic extract
  7. filtrationwas filtered through a pad of Na2SO4
  8. customevaporated in vacuo
  9. customto afford crude 5.(base) as a foam which
  10. dissolutionwas dissolved in 20 ml
  11. customCrystallization
  12. temperatureon cooling
  13. filtrationThe crystals were collected by filtration
  14. washwashed with 2×10 ml of cold ethyl acetate/n-hexanes (1:3), and oven
  15. customdried in vacuo at 60° C.

Sources & evidence

ORD record
ord-e21e9dee20f74f438d67f149e9a408d4
Source dataset
uspto-grants-1994_08
Patent number
US05336483

Reaction notes

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